Interesting article..in pain and can't sleep.....hope all is well...Mark

[Guest guest]

Chronic Pancreatitis

What is pain like in chronic pancreatitis? Here's a study from South Africa

which, if you just focus on the patients, out of the 172 with chronic calcific

pancreatitis due to alcohol: 80 with pain, roughly, and you can see that only a

very small minority had persistent chronic pain. That most patients have

recurrent or relapsing attacks of pain as the major manifestation of their

painful pancreatitis. Out of 207 with again alcoholic chronic pancreatitis.

Everybody has intermittent pain but generally this is short-lived and they will

often go months to years without any pain. In almost half of the patients, this

is the only pattern of pain. These patients did not require surgery. Fifty-six

percent of their cohort developed constant pain as defined here, needed an

operation, but the operation typically revolved around correction.

Either pseudocysts or cholestasis in the late phase. And this did lead to pain

relief. The argument here that persistent pain complicating chronic pancreatitis

should suggest a complication. This is the classic work, again from Amman, that

shows the natural history of alcoholic chronic pancreatitis, is that a lot of

patients - what percentage is not known - will have cessation of pain and that

generally correlates with the onset of pancreatic failure. As measured by

calcification, steatorrhea or diabetes. This is a somewhat contentious point but

I think that there's at least some hope that in the natural history that the

disease will take care.

Well, what about our experience? This is the study that came out a few years ago

in Gastroenterology looking at our cohort of patients. There are at least three

groups of chronic pancreatitis: the alcoholic with an onset in their 40's, and

then really two groups with idiopathic chronic pancreatitis. An early-age onset

group and a late onset pancreatitis. These groups differ based by the amount of

pain that they have. That is, the early onset idiopathic pancreatitic's almost

all present with pain. Much less frequently in this late onset group, so they

might present with pancreatic failure and the alcoholics were somewhere in the

middle. But it's really this group that we all struggle with the management.

This just in graphic form shows that this early onset tends to have the more

severe pain associated with their pancreatitis, as opposed to late-onset and the

alcoholic chronic pancreatitis.

Importantly, in terms of the natural history, those early onset chronic

pancreatitis patients take a long time to develop calcification, steatorrhea and

diabetes so they are going to have many years, or decades of pain before you can

realistically expect the pain to resolve. Now if you look again at those three

groups, what happens to them historically, they all have about the same rate of

pancreatic surgical procedures. Again, the other important thing here is that

out here at 20-25 years only about half of the patients have needed a surgical

procedure. But importantly again, in that early onset group the operation was

done for pain alone.

What about pancreatic hypertension? We know that the ductal and tissue pressures

are increased, and it's probably not just the duct. But really this is a

compartment syndrome because of fibrosis, entrapment, ischemia, which then leads

to pain. Importantly, there is really a poor correlation between the major duct

findings, the amount of dilatation and pain. A study from Reber in his

cat model shows that, in his model, the pressure in the gland as measured by the

interstitial pressure is high as is the duct pressure in his model. And then if

you only stent the main pancreatic duct there is really a modest change in the

pressure.

Now what about enzymes? I think it's based on the theory that secretion causes

pain in this compartment syndrome and that there is a feedback regulation in the

duodenum whereby proteases inhibit pancreatic secretion by digestion of a CCK

releasing factor. Easy to prove in the rat, more difficult to prove in man but I

think most people would agree that this operates at least at the extremes of

physiology. Does it work to treat pain? This from a metaanalysis of all of the

enzyme trials. Four of these studies were negative studies, two were positive.

Importantly the four negative studies used enterically coated enzyme

preparations. That you have to deliver proteases into the duodenum, which these

would potentially not do. This is from that metaanalysis and this is the study

from Florida. This is a Scandinavian study. These are the only two. In fact this

is the only one which reached statistical significance. Overall there was no

benefit, but again, these four studies used enterically coated enzymes. So I

think the jury is still out but I think we typically use them because it's

pretty benign therapy.

What about octreotide? You probably all know, there was a multi-center

controlled trial, 91 patients. Importantly, the placebo response was 40% overall

in this study, for painful chronic pancreatitis. There was no significant

differences overall. There was a trend in the very highest group - 200

micrograms t.i.d. - 65% versus 35%. In an open label study there was 50% pain

relief at six weeks, but again, remember the placebo response was 40%.

What about endoscopic stenting? Unproven, experimental. Again the morbidity has

to do with damaging the duct. Now if someone already has chronic pancreatitis

that's an arguable point, I suppose, but certainly you can get into infectious

complications with these procedures. This is a summary of the uncontrolled

trials, and I'll just say that the overall benefit approaches about 50%. And the

difficulty in interpretation is the intermittent nature of the pain, which we've

shown from the previous studies, and the placebo response of 40% seen in a drug

study.

What about taking stones out of the ducts? It looks very attractive. It's

technically feasible. Does that do anything to help pain? I think you are all

aware of uncontrolled studies from a variety of groups looking at both shock

wave lithotripsy as well as just endoscopic treatment. The pain relief, complete

or partial, runs in the 50-60% range. This gets at the pain relief so that

patients at the end of the study had not pain, but then if you look at the pain

that they had before the trial started, a few - 10% - had no pain, so I'm not

sure why they were getting the stones out, and you can see the majority of

patients who had intermittent pain often had infrequent attacks. Given the

natural history, how does one know without a controlled study, if you are really

doing any good? In the Cramier study, those patients are in the hospital on

average 14 days with this intervention. So again I think it is a therapy that is

of unknown benefit. So I think to summarize, it's uncertain if it is beneficial.

He would argue that the complications are unacceptable unless you are doing a

study, and it should certainly be done only by very experienced endoscopists and

probably only in large centers.

The other thing that complicates this whole field is the CFTR mutation finding

and how does that impact on the idea that somehow the sphincter of Oddi may be

important in these diseases, and I think it's going to take some time to sort

through how this fits into the management.

Just briefly, what about missed diagnoses? Don't forget there are other causes

for pain. IDMT, or intraductal mucin tumor, narcotic addition, other disorders.

We certainly see patients whose pancreatitis is defined by an abnormal sphincter

of Oddi measurement, and abdominal wall pain. This is a CT finding of IDMT which

could mimic chronic pancreatitis. Don't forget that of course the risk of

pancreatic cancer is higher in these chronic pancreatitis patients so that one

has to be alert to the possibility that they may have developed a complicating

carcinoma.